Substituted pyrrolo(2 3-d)pyrimidines and related compounds

ABSTRACT

THE DISCLOSURE IS DIRECTED TO SUBSTITUTED PYRROLO(2,3-D) PYRIMIDINES HAVING THE STRUCTURAL FORMULA   2-R4,4-(R1-NH-),5-(H2N-),6-R2,7-R3-7H-PYRROLO(2,3-D)   PYRIMIDINE   WHERE R1-R5 ARE AS DEFINED BELOW. THE COMPOUNDS HAVE PHARMACOLOGICAL ACTIVITY AS CENTRAL NERVOUS SYSTEM DEPRESSANTS IN THAT THEY DECREASE MOTOR ACTIVITY AND DECREASE RESPIRATION IN A HOST.

United States Patent Oflice Patented Dec. 28, 1971 3,631,044 SUBSTITUTED PYRROL[2,3-d]PYRIMIDINES AND RELATED COMPOUNDS Dong H. Kim, Wayne, and Arthur A. Santilli, Havertown, Pa., assignors to American Home Products Corporation, New York, NY. No Drawing. Filed Nov. 4, 1969, Ser. No. 874,049 Int. Cl. (307d 57/14 U.S. Cl. 260-2564 F 7 Claims ABSTRACT OF THE DISCLQSURE The disclosure is directed to substituted pyrrolo[2,3-d] pyrimidines having the structural formula I N TT ri -L R3 R Where R --R are as defined below. The compounds have pharmacological activity as central nervous system depressants in that they decrease motor activity and decrease respiration in a host.

1 0R6 i l 0 I 3 R R 0 N N N N 1 1 I where:

R is hydrogen or lower alkyl;

R is nitrile or methoxycarboximido;

R is chloro or lower alkoxy;

R is hydrogen or methoxy, with the proviso that R is methoxy when R is methoxycarboximido;

R is phenyl, halophenyl, lower alkylphenyl and lower alkoxyphenyl; and

R is methyl or ethyl.

described below, are reaction products of the above described compounds depicted by structural Formula 1:

N 00.11 E I NHR7 (III) where R and R are as defined above; and R is lower alkyl.

A typical example of the compounds of this invention which are depicted by structural Formula II is: 4-methoxy-6-methylamino-Z-phenyl 5 pyrimidinecarboxylic acid.

The new and useful compounds of this invention may be prepared by the process which is hereinafter schematically illustrated:

OH chlorination RB R5 IV V replacement J l replacement and rearrangement OR Ii -k L o N f 0N 1 l substitution a 0 00211 e I ru R t NEE I C=NH R VII VIII where R -R' are as defined above; and R is lower alkyl.

The 7- (lower) alkyl-Z-aryl-5-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-6-carbonitrile starting materials (1V) may be prepared as described in United States patent application, Ser. No. 752,486, filed Aug. 14, 1968 by Kim and Santilli, and entitled 7-Alkyl 2,5,6 Trisubstituted-7H-Pyrrolo [2,3-d]Pyrimidines and Related Compounds.

As shown in the schematic diagram, a 7-(lower)alkyl- 2-aryl-5-hydroxy-7H-pyrrolo[2,3-d]pyrimidine 6 carbonitrile (1V) compound is mixed with thionyl chloride and the mixture is heated for about 2 to 5 hours at the reflux temperature, preferably for about 3 hours. When the reaction is complete excess thionyl chloride is removed, for instance under reduced pressure, and the crude product is recrystallized, for instance from chloroform with charcoal treatment to produce a 7-(lower)alky1-2- aryl 6 chloro 5,6 dihydro-5-oxo-7H-pyrrolo[2,3-d] pyrimidine-G-carbonitrile (V).

The 7 (lower) alkyl-Z-aryl-6-chloro-5,G-dihydro-S-oxo- 7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (V) is mixed with an alkanol, and the mixture is heated at reflux temperatures for about /6 to 3 hours. Preferably the mixture is heated at reflux temperatures for about 30 minutes. When the reaction is complete, the reaction mixture is concentrated under reduced pressure and chilled causing separation of the product. The product is collected, for instance by filtration, and washed, for instance with alkanol to afford the crude product. The crude product may be recrystallized, for instance from absolute alkanol, to afford a pure product 6-(lower)alkoxy-7- (lower)alkyl- 2-aryl-5,6-dihydro oxo-7H-pyrrolo[2,3-d]pyrimidine- 6-carbonitrile (VI).

The 6 (lower)alkoxy-7-(lower)alkyl-2-aryl-5,6-dihydro 5 oxo-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (V1) is mixed with a solution of an alkali metal in methanol. While other metals may be used, as is known in the art, sodium and potassium are preferred because they will dissolve in the solvents being used and because they produce strong bases. The mixture is stirred at room temperature for about to 120 minutes and then is heated at reflux temperatures for about 10 to 120 minutes. Preferably the reaction mixture is heated at reflux temperature for about /2 hour.

When the reaction is complete the reaction mixture is chilled causing separation of precipitate which may be removed, for instance by filtration. The filtrate is concentrated under reduced pressure and chilled. The precipitate thus separated may be collected, for instance by filtration. The precipitate may be recrystallized, for instance from absolute alkanol, to afford a pure product 4,6-dimethoxy-7- (lower)alkyl-2-aryl 5,6 dihydro-S-oxo- 7H pyrrolo[2,3-d]pyrimidine-6-carboximidic acid, ester (VII).

The five-membered ring of the 4,6-dimethoxy-7-(lower) alkyl 2 aryl 5,6 dihydro 5 oxo-7H-pyrrolo[2,3-d] pyrimidine 6 carboximidic acid, ester (VII) may be opened by mixing the compound with a strong base, such as sodium hydroxide, and heating the reaction mixture at reflux temperatures for about /2 to 4 hours. Preferably the reaction mixture is refluxed for about 1 /2 hours. When the reaction is complete the reaction mixture is filtered to remove any insoluble material. The filtrate is neutralized to a pH of about 4 which causes the separation of a precipitate which may be collected, for instance by filtration. The precipitate may be purified by recrystallization, for instance from absolute alkanol, to afford the product 4 (lower)alkoxy-6-(lower)alkylamino-2-aryl-5- pyrimidinecarboxylic acid (VIII).

As is shown in the foregoing reaction scheme, an unexpected rearrangement occurs when the 7-(lower)alkyl- 2-aryl 6 halo 5,6 dihydro-5-oxo-7H-pyrrolo[2,3-d] pyrimidine-6-carbonitrile (V) is mixed with an alkanol containing an alkali metal. Methanol is the alkanol used where a desired substituent is methyl; ethanol is used where a desired substituent is ethyl, and so on. While other metals may be used, as is known in the art, sodium and potassium are preferred because they will dissolve in the solvents being used and because they produce strong bases. Addition of guanidine hydrochloride with the reactants has been found to improve the yield. The reaction mixture is stirred at room temperature for about /2 to 4 hours, preferably one hour, and then heated at about 60 to 90 C. for about 5 to 60 minutes. Preferably the reaction mixture is heated at reflux temperature for about minutes. When the reaction is complete, the reaction mixture is concentrated under reduced pressure and chilled. Crystals separate which may be collected, for instance by filtration, and washed, for instance with an alkanol and then with water to afford a crude product. Recrystallization of the crude product from an alkanol, such as methanol, affords the product 7-(lower)alkyl-2- aryl 5H pyrrolo[2,3-d]pyrimidine-5,6-(7H)-dione, 5- di(lower)alkyl acetal (II).

The foregoing products were evaluated for their pharmacological activity and it was found that the 7-(lower) alkyl 2 aryl 6 halo 5,6-dihydro-5-oxo-7H-pyrrolo [2,3-d1pyrimidine 6 carbonitriles (V); 4,6-di(lower) alkoxy-7-(lower)alkyl-2-aryl-5,6-dihydro 5 oxo 7H- pyrrolo[2,3-d]pyrimidine 6 carboximidic acid, esters (VII); and 7-(lower)alkyl 2 aryl-5-I-I-pyrrolo[2,3-d] pyrimidine-5,6-(7H)-dione, 5-di(lower)alkyl acetal (II) were active as central nervous system depressants. That is, they produce a calming effect in the host.

The 6 (lower)alkoxy-7-(lower)alkyl-2-aryl-5,6-dihydro-5-oxo-7I-I-pyrrolo[2,3-d]pyrimidine 6 carbonitriles (VI) are useful in the preparation of 4,6-di(lower)alkoxy- 7-(lower)alkyl-2-aryl-5,6-dihydro 5 oxo 7H-pyrrolo [2,3-d]pyrimidine-6-carboximidic acid, esters (VII). Also some of the compounds (VI) have pharmacological activity as central nervous system depressants, that is, they produce a calming effect in the host.

The 4 (lower)alkoxy 6 (lower)alkylamino-Z-aryl- S-pyrimidinecarboxylic acids (VIII) may be used to prepare the 4,6 di(lower)alkoxy-7-(lower)alkyl-2-aryl-5,6- dihydro-5-oxo-7H-pyrrolo[2,3-d1pyridimine 6 carboximidic acid, esters (VII).

In the pharmacological evaluation of the biological activity of the compounds of this invention, the in vivo effects are tested as follows. The compound is administered orally or intraperitoneally to three mice (14 to 24 grams) at each of the following doses: 400, 127, 40 and 12.7 mg./kg. The animals are watched for a minimum of two hours during which time signs of general stimulation (i.e., increased spontaneous motor activity, hyperactivity on tactile stimulation, twitching), general depression (i.e., decreased spontaneous motor activity, decreased respiration), autonomic activity (i.e., miosis, mydriasis, diarrhea) are noted.

The compounds of this invention induce central nervous system depressant effects at a dose of 127 to 400 milligrams per kilogram of host body weight (MPK) as evidenced by decreased motor activity and decreased respiration.

When the compounds of this invention are employed as described above, they may be administered alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk, sugar, certain types of clay and so forth. They may be administered sublingually in the form of troches or lozenges in which the active ingredient is mixed with sugar and corn syrups; and then dehydrated sufficiently to make it suitable for pressing into a solid form. They may be administered orally in the form of solutions which may contain coloring and flavoring agents or they may be injected parenterally, that is intra-muscularly, intravenously or subcutaneously. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for examples, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects.

In order more clearly to disclose the nature of the present invention, specific examples of the practice of the invention are hereinafter given. It should be understood,

The following example illustrates the preparation of 6- chloro-5,6-dihydro-7-methyl-2-phenyl-7H-pyrrolo [2,3 d] pyrimidine-6-carbonitrile, a compound of structural Formula V.

i 01 Curr N f N CH3 A mixture of 7.0 g. of 5-hydroxy-7-methyl-2-phenyl- 7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile and 75 ml. of

thionyl chloride was refluxed for 3 hr., then the excess I thionyl chloride was removed under reduced pressure. A remaining trace amount of thionyl chloride was removed in vacuo to give 6.9 g. of product having a melting point of 17 5-1 80. Recrystallization of the crude product from chloroform with treatment of charcoal afforded a product having a melting point of 183-185 Based on the assumed molecular formula C H ClN O, it was calculated that the elemental analysis by weight would be 59.06 percent carbon, 3.19 percent hydrogen, 19.68 percent nitrogen and 12.46 percent chloride. The product was analyzed and found to contain 59.27 percent carbon, 3.37 percent hydrogen, 19.47 percent nitrogen and 12.78 percent carbon which confirmed the accuracy of the assumed formula. This may be expressed:

Analysis.Calcd. for C H ClN O (percent): C, 59.06; H, 3.19; N, 19.68; Cl, 12.46. Found (percent): C, 59.27; H, 3.37; N, 19.47; Cl, 12.78.

When tested in the above-described pharmacological procedure, the product was found to decrease motor activity and decrease respiration at a dose of 127 MPK administered orally.

EXAMPLE II The following example illustrates the preparation of 7- butyl-6-chloro-5,6-dihydro-5-oxo-2-pheny1 7H pyrrolo [2,3-d]pyrimidine-6-carbonitrile, a compound of structural Formula IV.

7-butyl-6-chloro-5,6-dihydro-5-oxo-2-phenyl 7H pyrrolo[2,3-d]pyrimidine-6-carbonitrile was prepared as in Example I from 1.3 g. of 7-butyl-S-hydroxy-2-phenyl-7H- pyrrolo[2,3-d]pyrimidine-6-carbonitrile and 15 ml. of thionly chloride. The product was first recrystallized from anhydrous ether, then from heptane to give 0.7 g. of pure compound having a melting point of 125-128.

Analysis.Calcd. for C H ClN O (percent): C, 62.48; H, 4.62; N, 17.15; Cl, 10.85. Found (percent): C, 62.47; H, 4.71; N, 16.98; Cl, 10.63.

When tested in the foregoing pharmacological procedure, the product was found to decrease motor activity and decrease respiration at a dose of 127 MPK administered orally.

Following the procedure of Example II but substituting appropriate starting materials, compounds having the following substituents may be obtained:

Example EXAMPLE III The following example illustrates the preparation of 5,6-dihydro 6 methoxy 7-methyl-5-oxo-2-phenyl-7H- pyrrolo[2,3-d]pyrimidine-6-carbonitrile, a compound of structural Formula VI.

A mixture of 1.6 g. of 6-chloro-5,6-dihydro-7-methyl- 2-phenyl 7H pyrrolo[2,3-d]pyrimidine-6-carbonitrile and 55 ml. of absolute methanol was refluxed for 30 min., then concentrated to about 10' ml. under reduced pressure. Chilling of the concentrated solution caused separation of product which has collected on a filter and washed with methanol to give 1.6 g. of product having a melting point of 166169. Recrystallization from absolute methanol increased the melting point to 169-171".

Analysis.--Calcd. for C H N O (percent): C, 64.27; H, 4.32; N, 19.99. Found (percent): C, 64.39; H, 4.13; N, 20.31.

When evaluated in the above-described pharmacological procedure, the product was found to induce decreased motor activity and decreased respiration at a dose of 127 MPK administered parenterally.

EXAMPLE IV The following example illustrates the preparation of 6-ethoxy 5,6 dihydro 7-methyl-5-oxo-2-phenyl-7H- pyrrolo[2,3-d]pyrimidine-6-carbonitrile, a compound of structural Formula VI.

0 a gigg A mixture of 2.5 g. of 6-chloro-5,6-dihydro-7-methyl- Z-phenyl 7H pyrrolo[2,3-d]pyrimidine-6-carbonitrile, 45 ml. of absolute ethanol, and 0.5 g. sodium carbonate was refluxed for 1 hr., and filtered while hot. Chilling of the filtrate caused separation of a precipitate which was collected on a filter. Recrystallization of the crude product from absolute ethanol afforded an analytical sample having a melting point of 152.

Analysis.Calcd. for C H N O (percent): C, 65.29; H, 4.80; N, 19.04. Found (percent): C, 65.65; H, 5.17; N, 18.78.

EXAMPLE V The following example illustrates the preparation of 5,6 dihydro 6 isopropoxy 7-methyl-5-oxo-2-phenyl- 7H pyrrolo[2,3-d]pyrimidine 6 carbonitrile, a compound of structural Formula VI.

5,6-dihydro 6 isopropoxy 7 methyl 5-oxo-2- phenyl 7H-pyrrolo[2,3-d]pyrimidine 6 carbonitrile was prepared by the procedure of Example IV from 4.8 g. of 6 chloro 5,6-dihydro-7-methyl-2-phenyl-7H- pyrrolo[2,3-d]pyrimidine-6-carbonitrile and 150 ml. of isopropanol to give 4.5 g. of crude product having a melting point of 131-133. Recrystallization from absolute ethanol afforded the product.

Analysis.Calcd. for C H N O percent): C, 66.22; H, 5.23; N, 18.17. Found (percent): C, 66.28; H, 4.93; N, 18.53. 20

Following the procedure of Example III but substituting appropriate starting materials, compounds having the following substituents may be obtained:

EXAMPLE VI The following example illustrates the preparation of 5,6 dihydro-4,6-dimethoxy-7-methyl-5-oxo-2-phenyl-7H- pyrrolo [2,3-d]pyrimidine 6 carboximidic acid, methyl ester, a compound of structural Formula VII.

a (|)CH N *0 N =O Q Li OCH: L

N N O=NH N f C=NH (3H l on, 60 OCH;

Major Product Minor Product to l77179. 75

For the product the wave lengths of maximum absorption in infrared illumination when determined as a potassium bromide pellet were found to be 3.07 microns (a) indicating the presence of an NH group, at 5.82/L indicating the presence of a 0:0 group and at 5.99 4 indicating the presence of a CEN group. This may be expressed:

(I 3.07 (NH), 5.82 (CO) and 5.99 (CN).

The nuclear magnetic resonance (NMR) spectrum of the compound indicates three protons at 3.076, three protons at 3.306, three protons at 3.736, three protons at 4.236, three protons at 7.556, and three protons at 8.606. This may be expressed: NMR (6) CDCI 3.07 (s., 3H), 3.30 (s., 3H), 3.73 (s., 3H), 4.23 (s., 3H), 7.55 (m., 3H and 8.60 (m., 3H).

In' the mass spectrometer the ratios of mass to charge (m/e values) were found to be 342, 284, and 270. This may be expressed: Mass. spec. (m/e) 342, 284, 270.

Analysis.-Calcd. for C H N O (percent): H, 5.30; N, 16.37. Found (percent): C, 59.34; H, 5.45; N, 16.30.

When the product was evaluated in the above-described pharmacological procedure, it was found to induce decreased respiration and decreased motor activity at a dose of 127 MPK administered parenterally.

(B) As a minor product there was found 5,6-dihydro- 6 methoxy 7-methyl-5-oxo-2-phenyl-7H-pyrrolo[2,3-d] pyrimidine-G-carboximidic acid, methyl ester.

The precipitate (1.35 g.) which was isolated by chilling was analyzed and found to be 4-methylamino-2-phenyl-5- pyrimidine-carboxylic acid, methyl ester, having a melting point of 148-150".

Following the procedure of Example VI but substituting appropriate starting materials, compounds having the folmax EXAMPLE VII The following example illustrates the preparation of 4 methoxy 6 (methylamino)-2-phenyl-5-pyrimidinecarboxylic acid, a compound of structural Formula VIII. The product supports the structure of compound of Example VI by proving the presence of methoxy at the 4-position.

A mixture of 5,6 dihydro-4,6-dimethoxy-7-methyl-5- oxo 2 phenyl 7H-pyrrolo[2,3-d]pyrimidine-6-carboximidic acid, methyl ester (0.2 g.) and 10 percent aqueous sodium hydroxide (10 ml.) was refluxed for 1.5 hr., then filtered to remove any insoluble material. Neutralization of the filtrate to about pH 4 caused separation of a precip- EXAMPLE VIII The following example illustrates the preparation of 5,6-dihydro 6 methoxy-7-methyl-5-0xo-2-phenyl-7H- pyrrolo[2,3-d]pyrimidine--carboxylic acid, methyl ester, a compound of Formula VII.

major product I 2331 0 on. minor product A mixture of 5,6-dihydro-6-methoxy 7 methyl-S-oxo- 2-phenyl-7H-pyrrolo[2,3-d1pyrimidine 6 carbonitrile (2.3 g.), absolute methanol (30 ml.), and a catalytic amount of sodium (0.02 g.) was stirred at room temperature for 3.5 hr., then heated to reflux for 15 min. The reaction mixture was concentrated under reduced pressure and chilled in ice to cause separation of a precipitate which was collected on a filter to give 1.5 g. of 5,6-dihydro-G-methoxy 7 methyl-5-oxo-2-phenyl-7H-pyrrolo [2,3-d]pyrimidine-6-carboximidic acid, methyl ester having a melting point of 110120. Repeated recrystallization from absolute ethanol raised the melting point to 125- 127.

Analysis.-Calcd. for C H N O (percent): C, 61.53; H, 5.15; N, 17.94. Found (percent): C, 61.28; H, 5.14; N, 17.85.

Concentration of the mother liquor and subsequent chilling afforded a small amount of 5,6-dihydro-4,6-dimethoxy-7-methyl-5-oxo 2 phenyl-7H-pyrrolo[2,3-d] pyrimidine-6-carboximidic acid, methyl ester having a melting point of 177-179.

EXAMPLE IX The following example is a proof of the structure of the principal product of Example VIII.

N o N 00,03

ooH NH 45 \N N a \N C=NH on,

A mixture of 4-methylamino 2 phenyl-S-pyrimidinecarboxylic acid, methyl ester (0.29 g.), absolute methanol (7 ml.) and sodium (0.02 g.) was refluxed for 20 min. Chilling of the reaction mixture in ice caused separation of a precipitate which was collected on a filter and recrystallized from methanol to give 0.1 g. of 4-methylamino-Z-phenyl 5 pyrimidinecarboxylic acid, methyl ester having a melting point of 148-150". This compound is identical with an authentic sample prepared by refluxing S-carbethoxy 2 methylamino-2-phenylpyrimidine with methanol.

Analysis.Calcd. for C H N O (percent): C, 64.18; H, 5.39; N, 17.28. Found (percent): C, 64.14; H, 5.24; N, 17.16.

EXAMPLE X OCH L :ooH, Q \N To 50 ml. of anhydrous methanol containing 0.54 g. of sodium methoxide and 1.0 g. of guanidine hydrochloride was added 2.5 g. of 6-chloro 5,6 dihydro-7-methyl-2- phenyl-7H-pyrrolo[2,3-d1pyrimidine-6 carbonitrile. The resulting mixture was stirred at room temperature for 1 hr., refluxed for 50 min., then concentrated under reduced pressure, and chilled. Crystals were collected on a filter and washed first with ethanol, then with Water to give 1.7 g. of product having a melting point of 141-144. Recrystallization from methanol afforded a product hav ing a melting point of -142.

The same reaction was repeated without guanidine hydrochloride and equivalent results were obtained at lower yields.

Analysis.Calcd. for C H N O (percent): C, 63.15; H, 5.30; N, 14.73. Found (percent): C, 63.17; H, 5.21; N, 14.71.

When evaluated in the above-described pharmacological procedure, the product was found to decrease motor activity and decrease respiration at a dose of 400 MPK administered orally.

Following the procedure of Example X but substituting appropriate starting materials, compounds having the fol lowing substituents may be obtained:

1 1 What is claimed is: 1. A compound selected from those having the structure:

where:

R is hydrogen or lower alkyl;

R is nitrile or methoxycarboximido;

R is chloro or lower alkoxy;

R is hydrogen or methoxy, with the proviso that R is methoxy when R is methoxycarboximido; and

R is phenyl, halophenyl, lower alkylphenyl and lower alkoxyphenyl.

2. A compound as defined in claim 1 which is: 6-chloro- 5,6-dihydro-7-methyl 5 oxo 2 phenyl-7H-pyrrolo [2,3-d]pyrimidine-6-carbonitrile.

3. A compound as defined in claim 1 which is: 7-butyl- 6-chloro 5,6 dihydro-S-oxo-Z-phenyl 7H pyrrolo [2,3-d]pyrimidine-6-carbonitri1e.

4. A compound as defined in claim 1 which is: 5,6- dihydro-6-methoxy 7 methyl 5 oxo-2-phenyl-7H- pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

5. A compound as denfied in claim 1 which is: 6-ethoxy- 5,6-dihydro 7 methyl-S-oxo-Z-phenyl 7H pyrrolo [2,3-d]pyrimidine-6-carbonitrile.

6. A compound as defined in claim 1 which is: 5,6- dihydro-6-isopropoxy 7 methyl-5-oxo-2-phenyl 7H- pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

7. A compound as defined in claim 1 which is: 5,6- dihydro-4,6-dimethoxy 7 methyl-5-ox0-2-phenyl-7H- pyrrolo[2,3-d] pyrimidine 6 carboximidic acid, methyl ester.

References Cited UNITED STATES PATENTS 3,157,655 11/1964 Takamizawa et al. 260256.4 F

ALEX MAZEL, Primary Examiner R. J. GALLAGHER, Assistant Examiner U.S. Cl. X.R.

UNITED STATES PATENT @FFHIE RTIFICATE @F tt lN Patent No. 3, 631, O L I- Dated December 28 197 l nv n fl Done H. Kim and Arthur A. Santilli It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

I 2 At column 1, line #5 in formula I, R should read R as a? follows:

At column 2, informula III, the unsaturation between the l and 2 positions is omitted. Formula III should read as follows:

mg? UNrrED STATES PArrNr orrrcr fiERTlMQATE 0F (JGRRECHQN Patent No. 6' 1M Dated December 28 1971 Inv n fls) Done Kim and Arthur A. Santilli It is certified that error, appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

mt column 2, in formula IV, the unsaturation between the l l and 2 position is omitted. Formula IV should read as follows:

At column 2, in formula V, the unsaturation between the l and 2 position is omitted. Formula V should read as follows:

Signed and sealed this 20th day of June I972a (SEAL) Attest:

EDWARD FLFLETCHER IR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents 

